Masanori Yasuo

Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease

The aim of this study was to clarify the mechanism of increased airway inflammation during an acute exacerbation. A total of 68 chronic obstructive pulmonary disease patients in a stable phase were enrolled and followed-up for 2–3 yrs. Inflammatory cells were analysed, and interleukin (IL)-8, neutrophil elastase, eotaxin, tryptase and RANTES (regulated on activation, normal T-cell expressed and secreted) were measured in sputum, both in a stable phase and during acute exacerbation. Out of 68 patients, 30 (unstable group) developed an acute exacerbation and expectorated adequate sputum during exacerbation. Thirty-two patients (stable group) did not develop any exacerbation for 2–3 yrs. The number of neutrophils, lymphocytes and eosinophils, and the levels of IL-8, eosinophil cationic protein (ECP), eotaxin and tryptase in sputum obtained from patients in both groups during the stable phase were significantly higher than those from healthy nonsmokers. There were no significant differences in cell analysis and biomarkers between the two groups, but patients in the unstable group showed more severe airflow limitation. In the unstable group, total cells, lymphocytes, neutrophils and eosinophils, and IL-8, neutrophil elastase, ECP and RANTES levels were significantly increased during an exacerbation from values in a stable phase. These findings suggest that exacerbation of chronic obstructive pulmonary disease may associate with additional increases in airway inflammation mediated by neutrophils, lymphocytes, eosinophils, interleukin-8 and RANTES.

IgG4-related chronic rhinosinusitis: A new clinical entity of nasal disease

Abstract Conclusion: IgG4-related disease involves nasal manifestations with chronic rhinosinusitis (CRS). This type of sinusitis is a new clinical entity of nasal disease associated with a high level of serum IgG4 for which steroid therapy is effective. Objectives. To confirm whether IgG4-related disease has distinctive chronic rhinosinusitis. Methods: We compared serum IgG4 levels as well as nasal computed tomography (CT) and clinicopathological findings before and after glucocorticoid treatment in 31 patients diagnosed as having IgG4-related disease with nasal manifestations. To evaluate immunohistochemical findings of nasal mucosa, we compared them with IgG4-related CRS and common CRS. Results: All patients had levels of high serum IgG4. Ten of the 31 patients had nasal obstruction, nasal discharge, postnasal discharge, hyposmia, and dull headache. They also demonstrated sinus lesions on radiological findings. After glucocorticoid treatment, serum IgG and IgG4 levels were markedly decreased and along with improvement of the symptoms, nasal sinus CT findings also revealed improvement of the sinus opacification. In immunohistochemical examination, the magnitude of IgG4-positive plasma cell infiltration in common CRS was almost the same as in the IgG4-related CRS group. Therefore, in nasal mucosa immunocytochemical positive staining for IgG4 is not specific for definition of IgG4-related disease.

Relationship between Calcium-Activated Chloride Channel 1 and MUC5AC in Goblet Cell Hyperplasia Induced by Interleukin-13 in Human Bronchial Epithelial Cells

Background:Interleukin (IL)-13 has recently been reported as the major T-helper 2 cytokine involved in mucus overproduction and oversecretion in allergic airways. However, the relationship between human calcium-activated chloride channel-1 (hCLCA1) and MUC5AC induced by IL-13 in vitro has not been fully investigated. Objectives: The present study examines whether IL-13 induces the expression of hCLCA1 in normal human bronchial epithelial (NHBE) cells. We also investigated the relationship between hCLCA1 and MUC5AC expression and the development of goblet cell hyperplasia (GCH). Methods: NHBE cells were isolated from human bronchi, and cultured with an air-liquid interface. hCLCA1 and MUC5AC gene and protein expression, as well as GCH were examined in the cells after exposure to IL-13. Results: Incubation with IL-13 for 14 and 21 days increased the total number of epithelial cells, the number of periodic acid-Schiff (PAS)-stained epithelial cells, the number of goblet cells, as well as expression of mRNA and protein of hCLCA1 and MUC5AC. The number of goblet cells with secretory granules also increased after 21 days of incubation with IL-13. Niflumic acid, a chloride channel inhibitor, reduced mRNA expression of hCLCA1 and MUC5AC, and reduced the number of PAS-positive cells after incubation with IL-13. NHBE cells exposed or not to IL-13 expressed IL-13 receptor α1 (IL-13Rα1), and an antibody to IL-13 Rα1 also reduced the number of PAS-positive cells after exposure to IL-13. Conclusions: IL-13 might induce the expression of MUC5AC and hCLCA1 gene and protein in well-differentiated NHBE cells. These cells might also differentiate into goblet cells and become hyperplastic.

Modulation of mucus production by interleukin‐13 receptor α2 in the human airway epithelium

Background IL‐13 induces goblet cell hyperplasia and mucus overproduction in airway epithelial cells. IL‐13 receptor α2 (IL‐13Rα2) has been suggested to act as a ‘decoy receptor’ in the airway epithelium by inhibiting the IL‐13 signal. However, the regulatory mechanisms for mucus production by IL‐13Rα2 remain unclear.

Inhibition of histone deacetylase causes emphysema

In patients with chronic obstructive pulmonary disease (COPD), histone deacetylase (HDAC) expression and activity are reduced in the lung tissue. However, whether HDAC activity controls the maintenance of the lung alveolar septal structures has not been investigated. To explore the consequences of HDAC inhibition and address the question of whether HDAC inhibition causes lung cell apoptosis and emphysema, male Sprague-Dawley rats and human pulmonary microvascular endothelial cells (HPMVEC) were treated with trichostatin A (TSA), a specific inhibitor of HDACs. Chronic TSA treatment increased the alveolar air space area, mean linear intercept, and the number of caspase-3-positive cells in rat lungs. TSA suppressed hypoxia-inducible factor-1α (HIF-1α), VEGF, and lysyl oxidase (LOX) and increased microtubule-associated protein-1 light chain 3 (LC3), p53, and miR34a microRNA expression in both rat lungs and cultured HPMVEC. Gene silencing of HDAC2 using small interfering RNA (siRNA) in cultured HPMVEC resulted in the suppression of HIF-1α, VEGF, and LOX and an increase of p53 expression. These data indicate that HDAC inhibition causes emphysema and that HDAC-dependent mechanisms contribute to the maintenance of the adult lung structure. Our results also suggest that the increase in apoptosis, as a consequence of HDAC inhibition, is associated with decreased VEGF and HIF-1α expression.

Genetic Heterogeneity of EGFR Mutation in Pleomorphic Carcinoma of the Lung: Response to Gefitinib and Clinical Outcome

Somatic epidermal growth factor receptor (EGFR) mutations in exons 19 and 21 have been found in non-small cell lung cancer (NSCLC) and are associated with the therapeutic response to gefitinib in patients with advanced NSCLC. We report a case of pleomorphic carcinoma of the lung with different EGFR mutations. Prior to gefitinib treatment, an exon 19 deletion of EGFR mutation was positive in the specimens obtained from pleural effusion and left cervical lymph node, histologically proven to be adenocarcinoma. However, the response to gefitinib was poor and the patient died of progressive disease 4 months after the initiation of gefitinib therapy. Postmortem examination revealed the major histological component to be of the sarcomatoid or pleomorphic type with scant mixed adenocarcinoma, resulting in a histological diagnosis of pleomorphic carcinoma of the lung. Although the adenocarcinomatous tissue was still positive for exon 19 deletion of EGFR mutation alone, sarcomatous components had both the exons 19 deletion and 20 T790M mutation concomitantly, thought to be a gefitinib resistance mutation. Pulmonary pleomorphic carcinoma is a rare NSCLC composed of biphasic and heterogeneous malignant cell populations. The present case suggested that expression of different EGFR mutations is related to the biphasic histological appearance in pulmonary pleomorphic carcinoma.

Usefulness of Preoperative Endobronchial Ultrasound for Airway Invasion around the Trachea: Esophageal Cancer and Thyroid Cancer

Background: It is important to confirm preoperative tracheobronchial invasion to enable the selection of the most appropriate treatment. Objective: This study was performed to compare the usefulness of computed tomography (CT), magnetic resonance image (MRI) and bronchoscopy by endobronchial ultrasonography (EBUS) for the assessment of invasion of thyroid or esophageal cancer in cases with suspected tracheobronchial invasion. Methods: In cases with suspected contact between the tumor and tracheobronchial wall, CT, MRI and EBUS indicated deformity of the tracheobronchial wall due to the adjacent mass. The final diagnosis was based on surgical and histological results, and/or clinical follow-up. Results: Fifty-four patients were included in this study. Based on the findings of CT, MRI and EBUS, invasion was suspected in 29, 28 and 25 patients, respectively. Seventeen patients did not undergo surgery based on the results of CT, MRI and bronchoscopy with EBUS. Final diagnosis was intact trachea or bronchial adventitia in 26 patients and invasion in 28 patients. The sensitivity and specificity of CT, MRI and EBUS for invasion were 59 and 56, 75 and 73, and 92 and 83%, respectively. The accuracy of EBUS was significantly greater than that of CT in the present study (p = 0.0011). The accuracy of EBUS was significantly different from that of CT and MRI in the surgically treated patients (p = 0.005 and p = 0.032, respectively). Conclusion: EBUS is the most useful technique for determining the depth and extent of tumor invasion into the airway wall. The combination of MRI and EBUS will contribute to surgical planning in patients with esophageal and thyroid cancer.

Hypoxia inducible factor-1α in human emphysema lung tissue

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1&agr; in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n = 6; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n = 13; stage III and IV). We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1&agr; and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1&agr; and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1&agr; protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1&agr; protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry. In conclusion, reduced expression of HIF-1&agr; protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.

Comparative Study of Three Different Catheters for CT Imaging-Bronchoscopy-Guided Radiofrequency Ablation as a Potential and Novel Interventional Therapy for Lung Cancer

BACKGROUND We previously reported that bronchoscopy-guided, internally cooled radiofrequency ablation (RFA) in normal sheep lung was a safe, effective, and feasible procedure without major complications. PURPOSES The aim of this study was to evaluate the safety, effectiveness, and feasible conditions of bronchoscopy-guided, internally cooled RFA as a clinical application for non-small cell lung cancer (NSCLC). METHODS Ten patients pathologically diagnosed with NSCLC and the clinical stage of T1N0M0 were enrolled in the study. Three types of internally cooled electrode catheter tips were prepared using different procedure conditions involving ablation time: an internally cooled electrode with a 5-mm cylindrical active tip at a power output of 20 W, flow rate of 50 mL/min, and an ablation time of 30 s (n = 3), an electrode with an 8-mm active tip with four beads at 20 W, 50 mL/min, and 40 s (n = 3), and an electrode with a 10-mm active tip with five beads at 20 W, 50 mL/min, and 50 s (n = 4). CT image-guided, bronchoscopy-guided, internally cooled RFA was performed, and the patients underwent standard lung resection therapy. The resected lung tissue was examined histopathologically to assess the ablated areas. RESULTS Ablated areas pathologically evaluated with the 10-mm active tip were significantly larger than those with the 5-mm tip. Thus, the ablated areas were enlarged depending on the tip length and prolonged ablation time. There were no complications during RFA, such as bronchial bleeding or pneumothorax. CONCLUSIONS CT imaging-bronchoscopy-guided, internally cooled RFA in humans is a safe and feasible procedure that could become a potential therapeutic tool for local control in medically inoperable patients with stage I NSCLC.

Effects of PMX-DHP Treatment for Patients With Directly Induced Acute Respiratory Distress Syndrome

Abstract:  Endotoxin‐removal direct hemoperfusion column containing polymyxin B immobilized fibers (PMX‐DHP) is an effective procedure for the treatment of sepsis‐induced acute respiratory distress syndrome (ARDS). We investigated retrospectively the effects and appropriate timing of PMX‐DHP induction for directly induced ARDS in 38 patients. PMX‐DHP was carried out twice for two hours. Blood pressure, heart rate (HR) and PaO2/FIO2 (PF) ratio, leukocytes, platelets, endotoxin, inflammatory cytokines and clusters of differentiated peripheral neutrophils and monocytes were measured before and after PMX‐DHP. Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Sequential Organ Failure Assessment (SOFA) scores and lung injury scores (LIS) were determined at the time of starting PMX‐DHP. The underlying causes of ARDS were pneumonia in 29 patients and aspiration pneumonia in 9 patients. The patients were divided into Survivors (n = 21) and Nonsurvivors (n = 17). Mortality was 45% at 30 days after PMX‐DHP. The APACHE II and SOFA scores and the LIS were not significantly different between the two groups. The time from the onset of ARDS to the start of PMX‐DHP was significantly delayed between the two groups. PMX‐DHP significantly improved the PF ratio, HR and systolic blood pressure in the Survivors compared to the Nonsurvivors. The function of active monocytes in the peripheral blood was significantly suppressed after PMX‐DHP. This early induction of PMX‐DHP is indicated for directly induced ARDS. In the Nonsurvivors, this delay could have led to undesirable responses to oxygenation and circulation after PMX‐DHP.